Understanding the complexities of biological tissue and its electrical behavior continues to be an area of ongoing research and study. For example, a major challenge facing psychiatry is the lack of understanding of the neuronal network changes that underlie clinical depression and recovery. The hippocampus is hypothesized to play a central role in both depression pathophysiology and treatment response, but the underlying local network dynamics are not understood, with studies yielding apparently contradictory findings.
Development of new treatments for psychiatric disorders is hindered by an almost complete lack of information on how maladaptive neural physiology may give rise to affective phenotypes. For this reason, identification of a neurophysiological final common pathway linked to the etiology of a psychiatric disease could revolutionize understanding and guide clinical development of novel treatments. In depression, a leading cause of disability that affects an estimated 121 million people worldwide, the current widely-used medications are often effective in reducing symptoms and can promote remission, but treatment-resistance to first-line antidepressants like the selective serotonin reuptake inhibitors (SSRIs, such as fluoxetine and paroxetine) occurs in up to 50% of patients. Well-known medication side effects further complicate compliance and recovery, pointing to the need for new classes of treatment. Development of new classes of treatment is severely constrained by the incomplete understanding of the multifactorial biological etiology of depression, which involves genetic predisposition, epigenetic and developmental alterations, and adverse life events including chronic or acute stress. If many of these different etiological factors are expressed behaviorally through final common neurophysiological features, identification of these putative endophenotypes could not only provide a basis for understanding of the disease but also enable rapid development of novel selective classes of antidepressant treatments.
Candidate neural structures pertinent to depression physiology have been identified in part by using structural and functional imaging. Human fMRI studies have demonstrated altered blood flow associated with depression in several brain regions, including specific components of the emotion-regulating limbic circuitry. In particular, the hippocampus has received considerable attention as an integral component of the limbic system that communicates directly with and drives other brain regions implicated in depression, such as the prefrontal cortex, hypothalamic-pituitary-adrenal (HPA) axis, and reward centers. A substantial body of work favors the concept that the hippocampus is hyperactive in depression.
PET imaging has been used in depressed patients to implicate overactive excitatory pathways radiating from the hippocampus to downstream cortical regions (e.g., to Cg25) which is thought to be overactive in depression, and to orbitofrontal cortex), and furthermore found that fluoxetine-induced reduction in hippocampal activity was tightly linked to successful clinical response. Meta-analysis of functional brain imaging in medication treatment of depression indicated that changes in downstream cortical regions are delayed until specific adaptive changes occur in the source of primary afferent inputs, e.g., the hippocampus. This work showed that the hippocampus is a “primary site of action” for major antidepressants and a key initiator of successful response to antidepressant treatment. Complicating this picture, however, is evidence suggesting reduced hippocampal activity in depression, including reduced hippocampal size in clinical depression, the fact that excitatory hippocampal neurons display atrophy and death due to chronic stress and stress hormone exposure, and the observation that antidepressant-induced production of presumed excitatory neurons in the dentate gyrus of the hippocampal formation is linked to behavioral efficacy.